Effect of homocysteine and homocystine on platelet and vascular arachidonic acid metabolism.
Normal hemostasis depends in part on the balance achieved between proaggregatory and prothrombotic platelet thromboxane A2, measured as its stable end-product thromboxane B2 (TXB2), and vascular prostacyclin (PGI2), which inhibits platelet aggregation and is antithrombotic. Cystathionine-beta-synthase deficiency is characterized by a high frequency of thromboembolic disease. We therefore studied, in vitro, the effects of homocysteine and related compounds on platelet TXB2 and vascular PGI2 formation. In paired samples of platelet rich plasma, which had been preincubated with L-homocystine (1 mM), mean production of the two platelet cyclooxygenase products, TXB2 and 12-hydroxy-5, 8,10-heptadecatrienoic acid increased significantly from control levels [13.6% +/- 1.9 to 19.8% +/- 2.1 (P less than 0.02) TXB2 and 29.8% +/- 4.2 to 39.4% +/- 4.1 (P less than 0.01) HHT]. In the presence of D,L-homocysteine (1 mM), mean TXB2 and 12-hydroxy-5,8,10-heptadecatrienoic acid production was also significantly increased [12.7% +/- 1.5 to 16.9% +/- 1.5 (P less than 0.01) TXB2 and 27% +/- 4 to 31% +/- 4.1 (P less than 0.02) HHT]. Cystine, cysteine, or methionine (1 mM) did not have similar effects in this test system. Homocysteine and homocystine were without effect on the synthesis of vascular PGI2 by umbilical artery segments [control, 0.22 +/- 0.03 to 0.21 +/- 0.03 ng/mg with D,L-homocysteine and 0.20 +/- 0.04 control to 0.19 +/- 0.04 ng/mg with D,L-homocystine]. A homocyst(e)ine-induced increase in platelet thromboxane production in the absence of an increase in vascular prostacyclin, if present in vivo, may contribute to the vascular thromboses characteristic of human homocystinemias (homocystinurias).
D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000097:blood*; D001792:Blood Platelets / Q000378:metabolism*; D011464:Epoprostenol / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000097:blood; D006710:Homocysteine / Q000494:pharmacology*; D006711:Homocystine / Q000494:pharmacology*; D006801:Humans; D006880:Hydroxy Acids / Q000097:blood; D006893:Hydroxyeicosatetraenoic Acids; D008715:Methionine / Q000494:pharmacology; D013928:Thromboxane A2 / Q000097:blood; D014469:Umbilical Arteries / Q000378:metabolism*
D001095:Arachidonic Acids; D005231:Fatty Acids, Unsaturated; D006880:Hydroxy Acids; D006893:Hydroxyeicosatetraenoic Acids; D006710:Homocysteine; D016718:Arachidonic Acid; D006711:Homocystine; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; C008033:12-hydroxy-5,8,10-heptadecatrienoic acid; D013928:Thromboxane A2; D008715:Methionine; D011464:Epoprostenol